Core B: Mouse Management and Pathology Core The overall objective of the Mouse Management and Pathology Core is to provide pathogen-free and genetically standardized p66Shc(-/-) mice for the project, and to assess the age-related clinical and anatomic pathology of p66Shc(-/-) mice. In addition, we will carry out a lifespan study, on the lifespan of p66Shc, caloric restriction (CR), p66Shc+CR, and control animals in a barrier facility, which has not yet been carried out elsewhere. DC Davis is uniquely prepared to accomplish this objective with appropriate technical and faculty expertise, as well as program infrastructure. Specifically, we will (1) Expand breeding stock of congenic B6 p66Shc(-/-) mice to generate a colony of age and sex -matched p66Shc(-/-) mice and littermate controls for Aims II-IV. In the process, fully backcrossed embryos and germplasm will be cryopreserved to ensure against catastrophic loss of breeding stock and minimize genetic drift for future studies. (2) Assess the clinical and anatomic pathology of randomly sampled p66Shc(-/-) and littermate control mice at selected stages of life to determine age-related patterns of disease. Once sufficient numbers of congenic p66-/- and control mice have been established, mice will be bred for Project #4, which will sample mice at specific intervals for pathological, biochemical, and microarray analysis. This Core will process these valuable mice for full pathology analysis, to determine if all categories of pathology are retarded in the p66-/- mice or only if specific categories of pathology are retarded. Mice that are sampled at intervals will be subjected to hematology, clinical chemistry, and comprehensive anatomic pathology to assess age-related phenotypes. (3) Assess lifespan of control and caloric-restricted p66Shc(-/-) and wild type mice. Another cohort of p66Shc(-/-) and control mice will be established and maintained to determine lifespan in control and caloric- restricted conditions. The Mouse Management and Pathology Core will maintain these mice under barrier conditions. The results of this Aim will show if the mechanism by which p66 deficiency extends lifespan completely overlaps with CR, or not. (4) Provide an internet-accessible database to the scientific community on the age-related phenotype of p66Shc(-/-) and control mice. Data derived from Specific Aims II and III will be added to the DC Davis Mouse Biology Program website, including hematology, clinical chemistry, and anatomic pathology findings, and linked with the international Mouse Phenome Project. Relevance to public health: The conserved nature of the IGF-lnsR axis pathway for lifespan extension from flies to worms to mice, and the special focus of p66Shc on adiposity, suggests that elucidation of the p66Shc will likely be relevant to human health in the United States.